The invention relates to benzylidene derivatives, and more particularly to benzylidene cyclohexanone, benzylidene cyclopentanone, and benzylidene acetone, and derivatives thereof. The invention also relates to the biological activities of the aforementioned compounds in vivo and in vitro, pharmaceutical compositions thereof, and therapeutic methods of administration of same in animals.
Curcumin (structure shown below) has a dual effect in oxygen radical reactions; i.e., it can act as a scavenger of hydroxyl radicals or catalyze the formation of hydroxyl radicals depending on the conditions. Curcumin inhibits in vitro lipid peroxide formations by liver homogenates of edemic mice. The inflammatory response induced experimentally in animals appears to be correlated with disturbances of the regulation of cellular oxidative processes, as is evident from the anti-inflammatory action of well-known antioxidants. There is evidence of a parallel between edema formation in mice induced by carragenan and the in vitro production of lipid peroxides in liver cells. 
Thus, curcumin has been widely used medicinally as an anti-inflammatory, anti-bacterial, antioxidant, anti-hepatotoxic, hypochlolesterolanemia, anti-cyclooxygenase, anti-cancer, and radical scavenger agent. However, it has been reported that curcumin is not stable in an alkali (pH greater than 6.5) solution.
Toxicological studies indicate that curcumin is non-toxic at high doses. In contrast, certain pyrazolone compounds are much more toxic. For example, the use of aminophyrin as an anti-inflammatory was reported to be unsafe, because it could produce nitrosamine, a carcinogen. Dipyron, another pyrazolone derivative, is also known to give rise to adverse side effects such as agranulocytosis and allergic reaction. Similar side effects have been observed in still other by pyrazolone derivatives (phenazone, oxyphenylbutazone, phenylbutazone, etc.). The pharmacological and toxicological profile of phenylbutazone and its derivatives is illustrated below (J. Phar. Pharmacol, 1955, 7, 1002).
The present invention is based, at least in part, on the discovery that modification of the substituents on the aromatic rings of curcumin can affect that biological activity of curcumin. In particular, substitution on the aromatic rings of curcumin with electron donating and withdrawing groups increases anti-inflammatory activity.
Also, as noted above, curcumin is unstable at a pH above 6.5. It was postulated that the instability of curcumin at pH above 6.5 may be caused by the active methylene group. Accordingly, the present invention is also based, at least in part, on the discovery that modifying curcumin by deleting the active methylene and adjacent carbonyl group yields 1,4-pentadien-3-ones that are stable at pH above 6.5 and still possess advantageous biological, e.g., antioxidative, properties.
Therefore, in one aspect, the invention is a method for treating a responsive state in a subject. The method includes administering to a subject an effective amount of a compound of formula I such that said responsive state is treated, wherein said compound of formula I is: 
wherein
n is an integer from 0 to 3, and R1 and R2 are each independently selected from the group consisting of methyl, ethyl, isopropyl, tertiary butyl, hydroxy, chloro, trifluoromethyl, methoxy, and dimethylamine; and R3 is selected from the group consisting of methyl, ethyl, isopropyl, tertiary butyl, hydroxy, chloro, trifluoromethyl, methoxy, hydrogen, and dimethylamine; and pharmaceutically acceptable salts thereof.
In another aspect, the invention is directed to pharmaceutical compositions comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
In yet another aspect, the invention is directed to certain compounds of formula I, including 2,5-bis(4-hydroxy-3,5-dimethyl benzylidene)cyclopentanone, 2,5-bis(4-hydroxy-3,5-dimethoxy benzylidene)cyclopentanone, and pharmaceutically acceptable salts thereof